The specific aims of this research are: 1. to purify alpha-1-antitrypsins (alpha-1-AT) of the three major M-subtypes from plasma of individuals homozygous for one of these alleles; 2. to test the hypothesis that these slightly different glycoproteins have measurable differences in their ability to inhibit elastase; 3. to determine whether any specific M-subtype of alpha-1-AT is more susceptible to inactivating agents which have been shown to destroy elastase inhibitory capacity. The long-term objective of our studies is to investigate, using biochemical methods, the role of alpha-1-AT in susceptibility to disease. Serum deficiency of alpha-1-AT in PiZZ individuals is strongly linked to early emphysema. Even in individuals with normal serum levels of alpha-1-AT, there may be localized deficiencies of this protease inhibitor in tissues where leucocyte proteases have released large amounts of elastase and other hydrolytic and oxidative enzymes. The ability of diluted serum, representative of protein concentrations of extracellular fluid, to inhibit proteases should be studied. We have shown differences in inhibitory capacity toward porcine pancreatic elastase as a function of serum dilution in sera of the three M-subtypes of alpha-1-AT. We propose to continue these studies using the purified antiproteases and human leucocyte elastase and to extend them to test the susceptibility of the M-subtypes to agents which have been shown, in vivo and in vitro, to destroy elastase inhibitory capacity. These include oxidizing agents like those found in cigarette smoke and polluted air, and endogenous agents such as the peroxidase produced by neutrophils. Since over 90% of individuals with emphysema are of the M phenotype, the differences we have observed and will study may be relevant to the susceptibility of individuals of the M phenotype to emphysema.